A Proteomic Analysis of GSD-1a in Mouse Livers: Evidence for Metabolic Reprogramming, Inflammation, and Macrophage Polarization

Glycogen storage
disease type 1a (GSD-1a) is a rare genetic disease
caused by mutations in the catalytic subunit of the enzyme glucose-6-phosphatase-alpha
(G6Pase-α). The majority of patients develop long-term complications
including renal failure and hepatocellular adenoma/carcinoma. The
purpose of this study was to ascertain the proteomic changes in the
liver of LS-G6pc–/– mice,
a murine model of GSD-1a, in comparison with wild type mice to identify
potential biomarkers of the pathophysiology of the affected liver.
We used liquid chromatography-tandem mass spectrometry (LC-MS/MS)
to analyze liver lysates from a total of 20 LS-G6pc–/– and 18 wild type (WT) mice. We compared
the proteomic expression profile of LS-G6pc–/– and WT mice. We identified 4138 significantly expressed proteins,
1243 of which were differentially represented. Network and pathway
analyses indicate that LS-G6pc–/– livers display an age-dependent modulation of the expression of
proteins involved in specific biological processes associated with
increased progression of liver disease. Moreover, we found upregulation
of proteins involved in the process of tissue inflammation and macrophage
polarization toward the M2 phenotype in LS-G6pc–/– mice with adenomas. Our results identify
a metabolic reprogramming of glucose-6-P and a pathologic environment
in the liver compatible with tumor development and progression.